Exposure to radiation or invasive chemical agents causes serious cellular damage which has been virtually irreversible. Once exposed the tissue's ability to fight damaging effects of such exposures is greatly diminished if not eliminated.
Scientists have developed some promising and novel concepts to pre-condition mammals to be more resistant to such exposures. In EP 1 146 885 B1 Canadian Scientists from the University of Montreal developed a pre-conditioning treatment for mammalian patients to better withstand external cellular insults likely to effect acceleration of or to increase the degree of apoptosis or necrosis in the tissues or organs of the patient. More specifically against the harmful effects of chemical and radiation poisoning. Their objective was to provide a medicament for alleviating or decelerating the progression of symptoms of apoptosis or necrosis—related medical disorders. This patented technique is best described by a recitation of claim 1 which reads:
1. Use of an aliquot of blood from the mammalian body which has been extracted there from and reacted exvivo with at least one stressor selected from the group consisting of a temperature above or below body temperature, ultraviolet light and an oxidative environment for the manufacture of a medicament for use in alleviating or protecting against the symptoms of a disorder involving accelerated rates of apoptosis or necrosis in a mammalian body, said disorder, chemical exposure and ingestion disorder, neurodegenerative disorder, and physical trauma disorders, through reducing the rate of susceptibility to apoptosis or necrosis of tissues and organs of the mammalian body.
This procedure has noted benefits for pre-conditioning prior to exposure, but also notes benefits post-exposure.
In medicine a paradox occurs when one attempts to treat disorders with chemical or radiation. On the one hand dosages must be large enough to kill the infected site or tumorous growths while on the other hand limiting the migration or spill over which damages healthy non-affected tissues and organs.
Several prior art patents discuss at length the complications of such medical treatments. WO 021 069892 A2, an International publication by scientists at Temple University, discusses not only these therapeutic complications for a patient, but also radiation exposures to health care workers, dental practitioners, nuclear power plant workers and military personnel handling weapons or on nuclear powered vessels. Additionally this document discusses the well noted nuclear accidents such as Chernobyl, Tokamura and Three Mile Island as unintended exposures caused by power plant failures.
In WO 02/069892A2 it was stated “Pharmaceutical radiation sensitizers, which are known to preferentially enhance the effects of radiation in cancerous tissues, are clearly unsuited for general systemic protection of normal tissues from exposure to ionizing radiation.” These scientists from Temple University found that α,β-unsaturated aryl sulfones, in particular benzyl styryl sulfones, provide significant and selective systemic protection of normal cells from radiation-induced damage in animals. When used in radiotherapy techniques, these compounds also showed independent toxicity to cancer cells. A remarkably and potentially complimentary finding to those of the present invention as will be discussed in the detailed description of the present invention.
More sinister types of exposures where lethality is the primary objective are thermal nuclear wars and terrorist acts involving lower yield so called dirty bomb radiation dispersions. In these cases the objective was to kill or maim on a large scale.
U.S. Pat. No. 5,583,159 teaches the use of medicaments to prevent internal radiation damage by ingesting medicaments containing GLA and or DGLA is disclosed.
WO 2005/007118 A2 published on Jan. 27, 2005 by Regenerx Biopharmaceuticals, Inc. of Bethesda Md. teaches a method of treatment or prevention of damage due to radiation exposure comprising administering to a subject in need of such treatment an effective amount of a composition comprising 1) a compound including a radiation damage-inhibiting polypeptide comprising amino acid sequence LKKTET, a conservative variant of LKKTET, an actin-sequestering agent, an anti-inflammatory agent; 2) an agent which stimulates production of said compound in said subject; 3) an agent which regulates said compound in said subject; or 4) an antagonist of said compound, so as to inhibit radiation damage in said subject.
In accordance with one embodiment, this prior art invention includes the treatment, prevention or reversal of physical, cognitive, and biological injuries resulting from exposure to ionizing radiation by the use of the peptide, Thymosin beta 4 (Thymosin β4 or Tβ4), or fragments of Tβ4 such as LKKTET, or conservative variants thereof. Sometimes these are referred to as LKKTET peptides or polypeptides. Included are N-or C-terminal variants such as KLKKTET and LKKTETQ.
Tβ4 stimulates the production of laminin-5 in cells which may protect, or facilitate repair of, tissue. Tβ4 was initially identified as a protein that is up-regulated during endothelial cell migration and differentiation in vitro. Tβ4 was originally isolated from the thymus and is a 43 amino acid, 4.9 kDa ubiquitous polypeptide identified in a variety of tissues. Several roles have been ascribed to this protein including a role in a endothelial cell differentiation and migration, T cell differentiation, actin sequestration and vascularization.
Tβ4 has been localized to a number of tissue and cell types and thus, agents which stimulate the production of Tβ4 can be added to or comprise a composition to effect Tβ4 production from a tissue and/or a cell. Such agents include members of the family of growth factors, such as insulin-like growth factor (IGF-1), platelet derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor beta (TGF-β), basic fibroblast growth factor (bFGF), thymosin al (Tal) and vascular endothelial growth factor (VEGF). More preferably, the agent is transforming growth factor beta (TGF-β) or other members of the TGF-β superfamily. Tβ4 compositions of the invention may reduce certain effects of radiation by effectuating growth of the connective tissue through extracellular matrix deposition, cellular migration and vascularization.
Additionally, other agents may be added to a composition along with Tβ4 or a Tβ4 isoform. Such agents include angiogenic agents, growth factors, agents that direct differentiation of cells, agents that promote migration of cells and agents that stimulate the provision of extracellular matrix material in tissue. For example, and not by way of limitation, Tβ4 or a Tβ4 isoform alone or in combination can be added in combination with any one or more of the following agents: VEGF, KGF, FGF, PDGF, TGFβ, IGF-1, IGF-2, IL-1, prothymosin a and thymosin al in an effective amount.
The actual dosage or reagent, formulation or composition that heals damage associated with radiation damage may depend on many factors, including the size and health of a subject. However, persons of ordinary skill in the art can use teachings describing the methods and techniques for determining clinical dosages as disclosed in PCT/US99/17282, supra, and the references cited therein, to determine the appropriate dosage to use.
According to these prior art inventors, suitable formulations include the inventive composition at a concentration within the range of about 0.001-10% by weight, more preferably within the range of about 0.005-0.1% by weight, most preferably about 0.01-0.05% by weight.
The therapeutic approaches described therein involved various routes of administration or delivery of reagents or compositions comprising the Tβ4 or other compounds of this prior art invention, including any conventional administration techniques (for example, but not limited to, topical administration, local injection, inhalation, systemic or enteral administration), to a subject. The methods and compositions using or containing Tβ4 or other compounds of the invention may be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable non-toxic excipients or carriers.
All of these above referenced prior art treatments for damage prevention from exposure to radiation involve some form of medicament or radiation blocking medication.
An objective of the present invention is to compliment these radiation exposure pharmaceutical treatments by increasing the body's receptiveness to such treatments or to enable simplification of such drug compositions such that a drug induced activation of a healing cellular response mechanism is unnecessary altogether and thus such use of medicaments can be directed to treating the radiation or chemical agent induced effects of spreading infection and absorption of dead cells while the present invention complimentarily repairs and activates cellular repair and healthy cell regeneration to the exposed tissue and organs.